Adult Brain Tumor Consortium Research Articles

Evaluation of the Safety and Benefit of Phase I Oncology Trials for Patients With Primary CNS Tumors.

Patients with high-grade gliomas (HGG) are frequently excluded from first-in-human solid tumor trials because of perceived poor prognosis, excessive toxicities, concomitant drug interactions, and poor efficacy. We conducted an analysis of outcomes from select, single-agent phase I studies in patients with HGG. We compared outcomes to pooled analysis of published studies in solid tumors with various molecular and cytotoxic drugs evaluated as single agents or as combinations. Individual records of patients with recurrent HGG enrolled onto Adult Brain Tumor Consortium trials of single-agent, cytotoxic or molecular agents from 2000 to 2008 were analyzed for baseline characteristics, toxicities, responses, and survival. Our analysis included 327 patients with advanced, refractory HGG who were enrolled onto eight trials involving targeted molecular (n=5) and cytotoxic (n=3) therapies. At enrollment, patients had a median Karnofsky performance score of 90 and median age of 52 years; 62% were men, 63% had glioblastoma, and the median number of prior systemic chemotherapies was one. Baseline laboratory values were in an acceptable range to meet eligibility criteria. Patients were on the study for a median of two cycles (range, <one to 56 cycles), and 96% were evaluable for primary end points. During cycle 1, grade≥3 nonhematologic and grade≥4 hematologic toxicities were 5% (28 of 565 adverse events) and 0.9% (five of 565 adverse events), respectively, and 66% of these occurred at the highest dose level. There was one death attributed to drug. Overall response rate (complete and partial response) was 5.5%. Median progression-free and overall survival times were 1.8 and 6 months, respectively. Patients with HGG who meet standard eligibility criteria may be good candidates for solid tumor phase I studies with single-agent molecular or cytotoxic drugs with favorable preclinical rationale and pharmacokinetic properties in this population.

Outcome of Adult Brain Tumor Consortium (ABTC) prospective dose-finding trials of I-125 balloon brachytherapy in high-grade gliomas: challenges in clinical trial design and technology development when MRI treatment effect and recurrence appear similar.

The aim of this study is to define the maximal safe radiation dose to guide further study of the GliaSite balloon brachytherapy (GSBT) system in untreated newly diagnosed glioblastoma (NEW-GBM) and recurrent high-grade glioma (REC-HGG). GBST is a balloon placed in the resection cavity and later filled through a subcutaneous port with liquid I-125 Iotrex, providing radiation doses that diminish uniformly with distance from the balloon surface. The Adult Brain Tumor Consortium initiated prospective dose-finding studies to determine maximum tolerated dose in NEW-GBM treated before standard RT or after surgery for REC-HGG. Patients were inevaluable if there was progression before the 90-day posttreatment toxicity evaluation point. Ten NEW-GBM patients had the balloon placed, and 2/10 reached the 90 day timepoint. Five REC-HGG enrolled and two were assessable at the 90-day evaluation endpoint. Imaging progression occurred before 90-day evaluation in 7/12 treated patients. The trials were closed as too few patients were assessable to allow dose escalation, although no dose-limiting toxicities (DLTs) were observed. Median survival from treatment was 15.3 months (95 % CI 7.1-23.6) for NEW-GBM and 12.8 months (95 % CI 4.2-20.9) for REC-HGG. These trials failed to determine a maximum tolerated dose (MTD) for further testing as early imaging changes, presumed to be progression, were common and interfered with the assessment of treatment-related toxicity. The survival outcomes in these and other related studies, although based on small populations, suggest that GSBT may be worthy of further study using clinical and survival endpoints, rather than standard imaging results. The implications for local therapy development are discussed.

Timed-sequential therapy with mibefradil and temozolomide in patients with recurrent high-grade gliomas: A phase I Adult Brain Tumor Consortium study.

2033 Background: Mibefradil (MIB) is a selective T-type calcium channel blocker that had previously been approved for treatment of hypertension. MIB has shown significant preclinical activity in ma...

Repurposing and Rescuing of Mibefradil, an Antihypertensive, for Cancer: A Case Study

The expanding “valley of death” in drug development is leaving potentially life-saving new chemical entities and molecular targets fallow. This situation is forcing early-stage companies to think creatively about moving their technologies forward, especially as institutional investors show more interest in later stages of development. Drug repurposing, a strategy to examine existing drugs for therapeutic value against different diseases, is an emerging method to bring an off-market drug back onto the market. Tau Therapeutics LLC identified the role of T-type calcium channel blockers (Cav3) in cancer proliferation, but the company was unable to attract funding while having both a nonvalidated drug target and new chemical entities. To change the risk profile of the company, Tau set out to repurpose the known Cav3 drug mibefradil as a proof of concept for the treatment of cancer. Mibefradil was launched for hypertension in the 1990s but withdrawn because of drug–drug interactions. A new sequential combination treatment, termed Interlaced Therapy™, uses short-term administration of mibefradil to enhance the overall therapeutic potential of conventional anticancer agents. Mibefradil is currently in a phase Ib clinical trial with the National Cancer Institute (NCI) Adult Brain Tumor Consortium. Mibefradil has been repurposed from an abandoned antihypertensive to a targeted solid tumor treatment, and it has been rescued from drug–drug interactions by using short-term dose exposure. Tau is using the early success of mibefradil as a proof of concept to build a platform technology of Cav3 blockers for broad antitumor applications in combination with new targeted cancer therapies, well-established chemotherapies, and radiation.

Patterns of failure for glioblastoma multiforme following limited-margin radiation and concurrent temozolomide.

BackgroundTo analyze patterns of failure in patients with glioblastoma multiforme (GBM) treated with limited-margin radiation therapy and concurrent temozolomide. We hypothesize that patients treated with margins in accordance with Adult Brain Tumor Consortium guidelines (ABTC) will demonstrate patterns of failure consistent with previous series of patients treated with 2–3 cm margins.MethodsA retrospective review was performed of patients treated at the University of Alabama at Birmingham for GBM between 2000 and 2011. Ninety-five patients with biopsy-proven disease and documented disease progression after treatment were analyzed. The initial planning target volume includes the T1-enhancing tumor and surrounding edema plus a 1 cm margin. The boost planning target volume includes the T1-enhancing tumor plus a 1 cm margin. The tumors were classified as in-field, marginal, or distant if greater than 80%, 20-80%, or less than 20% of the recurrent volume fell within the 95% isodose line, respectively.ResultsThe median progression-free survival from the time of diagnosis to documented failure was 8 months (range 3–46). Of the 95 documented recurrences, 77 patients (81%) had an in-field component of treatment failure, 6 (6%) had a marginal component, and 27 (28%) had a distant component. Sixty-three patients (66%) demonstrated in-field only recurrence.ConclusionsThe low rate of marginal recurrence suggests that wider margins would have little impact on the pattern of failure, validating the use of limited margins in accordance ABTC guidelines.

Adult Brain Tumor Consortium (ABTC) Prospective Dose Finding Trials of I-125 Balloon Brachytherapy in Glioblastoma (GBM): The Problems in Trial Design When MRI Treatment Effect and Recurrence Appear Similar

Adult Brain Tumor Consortium (ABTC) Prospective Dose Finding Trials of I-125 Balloon Brachytherapy in Glioblastoma (GBM): The Problems in Trial Design When MRI Treatment Effect and Recurrence Appear Similar

Phase I adult brain tumor consortium (ABTC) trial of ABT-888 (veliparib), temozolomide (TMZ), and radiotherapy (RT) for newly diagnosed glioblastoma multiforme (GBM) including pharmacokinetic (PK) data.

2065 Background: ABTC conducted a dose finding trial of ABT-888, an orally administered Poly(ADP-ribose) polymerase [PARP] inhibitor, during daily TMZ with post-operative RT for GBM. PARP is important in repair pathways for RT induced DNA injury and TMZ induced alkylation at N7-methylguanine and N3-methyldenine. Methods: An initial safety group (no concurrent RT), received ABT-888 10 mg BID po during 42 days of daily TMZ 75 mg/m2. After this, the planned dosing steps included ABT-888 BID concurrent with standard RT and TMZ, with planned ABT-888 dose escalation or de-escalation based on observed toxicity. Dose limiting toxicity (DLT) is ≥ grade 3 non-hematologic or neurologic not responding to steroids, and hematologic ANC&lt;500/mm3 and platelets (PLT) &lt; 25K/mm3. The pharmacokinetics (PK) of ABT-888 were characterized for dose 1 and at steady-state. Results: Without concurrent RT, DLT (thrombocytopenia) occurred in 1/6 patients. With concurrent RT/TMZ and ABT-888 10 mg BID, 4/12 patients had DLT (thrombocytopenia). As per the planned dose de-escalation, ABT-888 10 mg BID was then given every other week during TMZ/RT. This resulted in 3/6 patients with DLT (2 thrombocytopenia, 1 neutropenia). The hematologic toxicity with this regimen was judged high enough that accrual was discontinued. In the setting of continuous dosing for 6 weeks, the total body clearance of ABT-888 for the first dose (27.5±9.5 L/h, n = 15) and at steady-state after BID dosing (23.5±10.4 L/h, n = 18) were similar. Accumulation for BID dosing was 56±33%. Steady-state peak and trough concentrations of the drug in plasma were 66±29 ng/mL and 18±10 ng/mL, respectively. Additional PK data will be presented. Conclusions: Administering ABT-888 BID po in combination with standard RT/TMZ was not tolerable in GBM patients as a result of hematologic toxicity. ABT-888 PK in GBM patients were very similar to findings reported for solid tumor patients. There is strong scientific rationale for continued development of an appropriate dosing regimen for this agent in the initial therapy of GBM. Clinical trial information: NCT00770471.

A phase I study of cediranib in combination with cilengitide in patients with recurrent glioblastoma.

2054 Background: Despite high vascularity, duration of response of glioblastoma (GBM) to anti-angiogenic therapy is short. One proposed mechanism of resistance is via co-option of native brain blood vessels and tumor infiltration into normal appearing brain. We designed a Phase I study of cediranib, a VEGFR tyrosine kinase inhibitor, in combination with cilengitide, an integrin inhibitor, to block this infiltrative relapse. Methods: A phase I study was conducted through the Adult Brain Tumor Consortium in patients with recurrent GBM. Once the MTD was determined, 40 patients enrolled in a dose expansion cohort. Standard eligibility criteria were included and all patients needed to have at least 1 cm of residual disease to assess tumor response. In the dose expansion cohort, 20 patients had received prior anti-VEGF therapy and 20 had never received anti-VEGF therapy. The primary endpoint was the safety of cediranib with cilengitide. Secondary endpoints were overall survival, the proportion of patients alive and progression free at 6 months (APF6), radiographic response (RR), and exploratory analyses of advanced MRI (perfusion, permeability, diffusion imaging) and blood biomarkers. Results: Forty-five patients were enrolled with a median age of 54 (23-80) and a median KPS 80 (60-100). No DLTs were observed and the MTD was cediranib 30mg daily and cilengitide 2000 mg twice weekly. There were no unexpected Grade 3 or 4 toxicities. Thirty patients experienced disease progression, 8 patients went off study for toxicity, and 5 patients withdrew from the study. Thirty nine patients have died. Partial response was seen in 2 patients, stable disease in 13, progression in 21, and 7 patients were not evaluable for RR. Median OS was 6.4 months, median PFS was 2.4 months, and APF6 was 7.5%. Conclusions: Combination cediranib/cilengitide was well tolerated but the median PFS/OS, APF6, and RR were not very promising. Ongoing analysis of the correlative imaging and blood biomarkers may shed light on a subset of patients who might benefit from this regimen and if anti-VEGF therapy blocked the penetration of cilengitide into the tumor. Clinical trial information: NCT00979862.

Sequential therapy with the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas: An Adult Brain Tumor Consortium phase I study (ABTC1101).

TPS2105 Background: Despite recent advances in their treatment, high-grade gliomas (HGG) carry a dismal prognosis. Treatment options at recurrence are particularly limited and a re-challenge with temozolomide (TMZ) frequently appears as the most appropriate systemic treatment option in patients whose progression occurred off TMZ. This study investigates the sequential treatment of mibefradil (MIB), a selective Cav3 calcium channel blocker, and standard dose TMZ. Preclinical data showed that Cav3 inhibitors such as MIB can slow tumor growth without significant effect on normal tissues and can induce cell cycle arrest in cancer cells at the G1/S-phase checkpoint. We hypothesize that withdrawal of MIB could synchronize and release cells into S-phase, thereby potentiating the cytotoxic effect of TMZ. Methods: This trial is an open-label, multicenter phase I study, structured into a dose escalation phase to determine the maximum tolerated dose of MIB (MTD; Primary Objective) and an expansion cohort of 10 patients at the MTD level. Adults with recurrent HGG (WHO grade 3 or 4) who have previously received standard adjuvant therapy with radiation (RT) and TMZ (last dose ≥ 3 months prior to enrollment) and who have not received other cytotoxic therapy (except for carmustine wafers) are eligible. Patients receive oral MIB for 7 days on a 4 x/day (QID) schedule, followed by standard dose TMZ at 150-200 mg/m2 for 5 days each 28-day cycle. Dose finding uses a modified 3+3 design, starting at MIB 25 mg po QID (100 mg/day) with dose increases of 25 mg/dose per dose level. The target dose-limiting toxicity (DLT) rate is ≤ 33%. Secondary Objectives: (1) safety and adverse event analysis (incl. cardiac monitoring during cycle 1), (2) pharmacokinetic profile of MIB, (3) response assessment (RANO criteria), and (4) assessment of the potential effect of MIB on tumor DNA synthesis as determined by fluorothymidine positron emission tomography (FLT PET; extension cohort). Enrollment status as of January 2013: cohort 1 completed without DLT; cohort 2 enrolling at MIB 200 mg/day. Clinical trial information: NCT01480050.

Phase I study of aflibercept (VEGF Trap) and temozolomide in newly diagnosed, high-grade glioma.

2043 Background: Anti-vascular endothelial growth factor (VEGF) therapy has shown promise in the treatment of high-grade gliomas (HGG). Aflibercept is a recombinant human fusion protein that acts as a soluble decoy receptor for VEGFA, VEGF-B and placental growth factor (PlGF), depleting circulating levels of these growth factors. Methods: The Adult Brain Tumor Consortium (ABTC) conducted a phase I trial of aflibercept and temozolomide (TMZ) in patients with newly diagnosed high-grade gliomas (HGG). Three cohorts were examined: Cohort 1: Aflibercept with radiotherapy and concomitant temozolomide; Cohort 2: Aflibercept and adjuvant temozolomide using the 5/28 regimen; and Cohort 3: Aflibercept and adjuvant temozolomide using the 21/28 day regimen. Eligibility criteria included histologically proven newly-diagnosed glioblastoma (GBM) or anaplastic glioma (AG), > 18 yrs old, KPS > 60, adequate bone marrow reserve and organ function. Patients initially received 2 mg/kg of aflibercept every 2 weeks. If no dose-limiting toxicities (DLT's) were observed the dose was increased to the single agent dose of 4mg/kg every 2 weeks in the next cohort of patients. No further dose escalation was permitted. Dose-finding used a standard 3 + 3 design with the MTD defined as the dose where DLT's occurred in fewer than 1/6 patients. At least 6 patients were treated at the MTD. Once this was defined, an additional 9 patients were treated for a total of 15 patients. Results: To date 48 patients have been enrolled, of whom 43 were evaluable. Median age was 56.9 years (23.91-69.19); median KPS 90 (70-100). The MTD of aflibercept for all 3 cohorts was 4mg/kg every 2 weeks. DLTs at the MTD were: Cohort 1: 0/6 patients; Cohort 2: 2/15 patients (G3 DVT, G4 ANC; Cohort 3: 3/15 patients (G4 biopsy-confirmed thrombotic microangiopathy; G3 rash, G4 thrombocytopenia). Conclusions: The combination of aflibercept and TMZ was generally well tolerated. The recommended phase II dose of aflibercept with radiotherapy and concomitant and adjuvant temozolomide is 4mg/kg every 2 weeks.